Process for producing polyene compounds

ABSTRACT

A PROCESS FOR PRODUCING 3 - METHYL - 5 - (1-HYDROXY2,6,6 - TRIMETHYL - 4 - OXO - CYCLOHEX-2-EN-1-YL)-PENTA-2,4DINE-1-OIC ACID, DERIVATIVES THEREOF AND RELATED COMPOUNDS WHICH ARE USEFUL AS PLANT GROWTH REGULATORS, FROM 4-(1,2EPOXY-2,6,6 - TRIMETHYL - CYCLOHEX - 3 - EN-1-YL)-BUT-3-EN2-ONE OR 3 - METHYL - 5 - (1,2 - EPOXY-2,6,6-TRIMETHYLCYCLOHEX-3-EN-1-YL)-PENTA-2,4-DIENYL DERIVATIVES INCLUDING INTERMEDIATES IN THIS PROCESS.

United States Patent 3,793,375 PROCESS FOR PRODUCING POLYENE COMPOUNDSUlrich Schwieter, Reinach, Basel-Land, and Norbert Rigassi, Arlesheim,Switzerland, assignors to Holfmann- La Roche Inc., Nutley, NJ.

No Drawing. Filed June 18, 1970, Ser. No. 47,572 Claims priority,application Switzerland, July 4, 1969, 10,221/69 Int. Cl. C07c 49/61 US.Cl. 260-587 4 Claims ABSTRACT OF THE DISCLOSURE A process for producing3 methyl (l-hydroxy- 2,6,6 trimethyl 4 oxocyclohex-Z-en-l-yl)-penta-2,4- dien-l-oic acid, derivatives thereof andrelated compounds which are useful as plant growth regulators, from4-(l,2- epoxy-2,6,6 trimethyl cyclohex 3 en-l-yl)-but-3-en- 2-one or 3methyl 5 (1,2 epoxy-2,6,6-trimethylcyclohex-3-en-l-yl)-penta-2,4-dienylderivatives including intermediates in this process.

BACKGROUND OF THE INVENTION In the past 1 hydroxy 2,6,6trimethyl-4-oxo-cyclohexene compounds have been manufactured withdifficulty and in poor yields. For example, 4 (l-hydroxy-2,6,6-trimethyl4 oxo cyclohex 2 en-1-yl)-but-3-en-2-one [6 hydroxy 3 keto a-ionone] hasbeen prepared by oxidizing 4 (2,6,6 trimethyl-cyclohex-Z-en-1-yl)-but-3-en 2 one [a-ionone] with t-butyl chromate or chromic acid. Thisoxidation has only produced the desired 6-hydroXy-3-keto a ionone inpoor yields. Furthermore, the 6-hydroxy-3-keto-u-ionone obtained by thisprocess has been diificult to isolate in pure form.

Additionally, the known plant growth regulator, abscisic acid, [3 methyl5 (1 hydroxy-2,6,6-trimethyl-4-oxocyclohex 2 en 1yl)penta-2-cis-4-trans-dien-loic acid] has in the past been prepared byfirst converting 3- methyl 5 (2,6,6 trimethyl cyclohexa-l,3-dien-1-yl)-penta-2,4-dien-1-oic acid into 3-methyl 5 (1,4-epidioxy- 2,6,6 trimethylcyclohex 2 en-1-yl)penta-2,4-dienoic acid by photochemical oxidation,then opening the endoperoxide with a base and thereafter separating thedesired 2-cis isomer from the 2-cis/trans isomeric mixture. This processsuffers from the disadvantage that it produces abscisic acid in pooryields and that extensive purification of the abscisic acid produced bythis process is necessary.

SUMMARY OF THE INVENTION In accordance with this invention it has been:found that compounds of the formula X is hydroxymethylene, formyl,cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, phenoxycarbonyl,phenoxycarbonyl substituted with at least one member selected from thegroup consisting of nitro, lower alkyl, halo lower alkyl ,or loweralkylsulfonyl, benzoyl, benzoyl substituted with at least one memberselected from the group consisting of lower alkyl, nitro, halo loweralkyl or lower alkyl-sulfonyl, or

and R and R are individually hydrogen, lower alkyl or phenyl or takentogether with their attached nitrogen atom form an imidazole ring can beobtained in high yields and which a high degree of purity in a simplemanner by first reacting a compound of the formula wherein X isetherified or esterified hydroxymethylene, formyl, cyano, carboxy, loweralkoxycarbonyl, lower alkanoyl, phenoxycarbonyl, phenoxycarbonylsubstituted with at least one member selected from the group consistingof nitro, lower alkyl, halo lower alkyl, or lower alkylsulfonyl,benzoyl, benzoyl substituted with at least one member selected from thegroup consisting of lower alkyl, nitro, halo lower alkyl or loweralkylsulfonyl or and R and R are individually hydrogen, lower alkyl orphenyl or taken together with their attached nitrogen form an imidazolering with selenium dioxide and then oxidizing the resulting 1,4-diol. Ifthe compound of Formula I is formed where X is an etherified oresterified hydroxymethylene group; this group can be hydrolized to formthe corresponding alcohol. If the compound of Formula I above is formedwhere X is an esterified acid group, these esters can, if desired, besaponified and, if desired, the resulting acid converted into an amideor an ester.

In accordance with this invention, the above process provides a simpleand economic means for producing the known plant hormones such asabscisic acid, abscisic acid derivatives and related compounds asillustrated by Formula I above.

The compounds of Formula I are useful as plant growth regulatory agents.

Among the preferred compounds of Formula I produced by this inventionare the following:

4-( 1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-Z-en-l-y1)- but-3-en-2-one[6-hydroxy-3-keto-a-ionone];

3-methyl-5- l-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-2-en-l-yl)-penta-2-cis,4-trans-dien-l-oic acid [abscisin];

3 -methyl-5- 1-hydroxy2,6,6-trimethyl-4-oxo-cyclohex-2-en-1-yl)-penta-2-cis/ trans, 4-trans-dien-1-oic acid ethyl ester;

3-methyl-5-( l-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-Z-en-2-yl)-penta-2,4-dien-l-oic acid methyl ester;

3-methyl-5-( 1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-Z-en-l-yl)-penta-2,4-dien-1-oic acid n-pentyl ester;

3-methyl-S-( 1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-2-en-l-yl)-penta-2,4-dien-1-oic acid phenyl ester;

DETAILED DESCRIPTION OF THE INVENTION The term halogen as usedthroughout this application includes all four halogens, i.e., bromine,chlorine, fluorine and iodine, if not otherwise indicated. As usedthroughout this application, the term lower alkyl comprehends bothstraight and branched chain saturated hydrocarbon groups containing from1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, etc. Theterm lower alkoxy comprehends lower alkoxy groups containing from 1 to 6carbon atoms such as methoxy, propoxy, ethoxy, etc.

The term lower alkanoyl as utilized throughout this specificationincludes lower alkanoyl groups containing from 1 to 6 carbon atomspreferably 1 to 5 carbon atoms. Among the preferred lower alkanoylgroups are included acetyl, propionyl, pivaloyl.

The term lower alkoxycarbonyl .groups includes groups wherein lowerall;oxy is defined as above. The preferred lower alkoxycarbonyl groupsare those groups wherein the lower alkoxy substituent contains from 1 to5 carbon atoms, such as methoxycanbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or pentoxycarbonyl.

The lower alkyl residue, the lower halo alkyl residues, and the loweralkyl sulfonyl residues which can be substituted on the phenylsubstituent can contain from 1 through 6 carbon atoms, preferably from 1to 4 carbon atoms. The halo lower alkyl residue can bemonohalosubstituted, dihalo-substituted or trihalo-substituted. Amongthe preferred halo alkyl residues are included chloromethyl,dichloromethyl, and trifluoromethyl. Among the lower alkyl sulfonylresidues are included, methyl sulfonyl, and ethyl sulfonyl.

The carbamyl group can be mono-substituted or disubstituted by loweralkyl. Among the preferred lower alkyl substituted carbamyl groups arethose wherein the lower alkyl substituent contains from 1 to 4 carbonatoms. Among such groups are included methyl carbamyl, N,N- dimethylcarbamyl, ethyl carbamyl and N,N-diethy1 carbamyl.

The X in the compound of Formula II above is an etherified or esterifiedhydroxymethylene group, the hydroxymethylene group can be etherifiedwith a lower alkyl or aryl substituent. 0n the other hand, thehydroxymethylone group can be esterified with a lower alkanoyloxy oraryloxy group. The term aryl as used throughout the application includesmono-nuclear aryl groups such as phenyl which can be unsubstituted orsubstituted in one or more positions with lower alkyl, halogen or nitro.The term ary also includes polynuclear aryl groups, such as naphthyl,anthryl, and phenanthryl, azulyl, etc. which may be unsubstituted orsubstituted with one or more of the aforementioned groups. The preferredpolynuclear aryl group is naphthyl.

The compounds of Formula I are hormones for promoting the abscission orshedding of the fruit from a plant and for regulating the growth ofplants. The compounds of Formula I are growth regulators for mono anddicotyledonous plants. Furthermore, because of their low toxicity thesecompounds also can be used as herbicides.

The compounds of Formula I are preferably employed in the cultivation ofsugar cane. By applying these compounds to sugar cane, the sugar contentof the sugar cane can be enhanced since these compounds inhib t thegrowth of the shoots.

The compounds of Formula I Where R is CH; -CH=OH-('J=OHX' wherein X isas above, have the formula wherein X is as above.

The compounds of Formula I-A can be produced from compounds of theformula by the following reaction scheme:

0 (\A/ OH OH 0 0 VIII I-A wherein X is as above.

The compound of Formula V can be converted to the compound of FormulaVI, by a reaction step (a) by treating the compound of Formula V with anorganic peracid. In carrying out this reaction, any conventional organicperacid can be utilized. Among the conventional organic peracids whichcan be utilized, performic acid, peracetic acid, perbenzoi-c acid,m-chloro-perbenzoic acid and perphthalic acid are preferred. Generallythis reaction is carried out in the presence of an inert organicsolvent. Any conventional inert organic solvent can be utilized incarrying out this reaction. Among the pre ferred inert organic solvents,the halogenated hydrocarbon solvents such as methylene chloride arepreferred. In carrying out these reaction temperatures of from -l0 C. toroom temperature are generally utilized. Generally, it

5 is preferred to utilize temperatures of about C. in carrying out thisreaction.

By the process of step (a),4-(2,6,6-trimethyl-cyclohexa-l,3-diene)-but-3-en-2-one[dehydro-B-ionone] is converted to 4 (1,2epoxy-2,6,6-trimethyl-cyc1ohex-3-en-1- yl) -but-3 -en-2-one [5,6-epoxy-dehydro-B-ionone] The compound of Formula VI can be convertedto the compound of Formula VII, via reaction step (b) by treating thecompound of Formula VI with selenium dioxide. The epoxide of Formula VIand selenium dioxide can, if desired, be employed in equal molaramounts. However, it has been found to be expedient to use the seleniumdioxide in a molar excess of the amount of the compound of Formula VI.Generally, it is preferred to use about 1 mole to about 2 moles ofselenium dioxide per mole of the compound of Formula VI in carrying outthe reaction of step (b). The reaction of step (b) is carried outpreferably in an organic solvent. Any conventional organic solvent canbe utilized. Among the preferred organic solvents are includedtetrahydrofuran, dioxane, diethyl ether, hexane, benzene, etc. withtetrahydrofuran being especially preferred.

The selenium dioxide, which exists as a solid at room temperature, isadvantageously utilized in a finely divided form, especially in apulverized form. In carrying out the reaction of step (b), temperatureand pressure are not critical and the reaction can be carried out atroom temperature and atmospheric pressure. However, if desired, elevatedor reduced temperatures can be utilized. Generally, it is preferred tocarry out this reaction at a temperature of from 0 C. to the boilingpoint of the reaction mixture. Depending upon the chosen reactiontemperature, from about 12 to 60 hours are sufiicient to carry out thereaction of step (b).

The compound of Formula VII can be isolated from the reaction mixture ofstep (b) by the conventional means. These means included extracting witha solvent [particularly diethylether], washing the extract with dilutealkali, drying and thereafter evaporating the ether solvent. Thecompound of Formula VII can, if desired, be purified by conventionalmeans such as adsorption on Kieselgel and elution with a solventmixture, such as hexane and ethyl acetate. On the other hand, the crudecompound of Formula VII can be oxidized to the compound of Formula VIII.

The oxidation of either the pure or crude compound of Formula VII to thecompound of Formula VIII can be carried out by use of various oxidizingagents. Among the preferred oxidizing agents are included chromium orsulfur trioxide and pyridine, manganese dioxide, chromisulfuric acid,dimethylsulfoxide or N-bromo lower alkanoyl amides. Among the preferredN-bromo lower alkanoyl amides, N-bromoacetamide, is especiallypreferred. In carrying out this reaction any of the conventionalconditions utilized in carrying out oxidation reactions with theseoxidizing agents can be utilized.

From the aforementioned agents, chromisulfuric acid is generallypreferred. Inutilizing this oxidizing agent, one expediently uses achromisufuric acid solution prepared from 26.72 grams of chromiumtrioxide, 23 ml. of concentrated sulfuric acid and 'water to 100 m1.This oxidizing agent is conveniently allowed to act on the compound ofFormula VII at a temperature of from to 10 (3., preferably at about 0 C.This oxidation can be completed after a few minutes, i.e., after aperiod of from about 5 to minutes. The reaction mixture can be worked upin a conventional manner such as by pouring the reaction mixture ontoice water and extracting with diethyl ether. The ether extract can thenbe washed, dried and the ether evaporated therefrom. If desired, thecompound of Formula VIlT can be purified by adsorption on Kieselgel andeluting with a solvent mixture preferably hexane and ethyl acetate.

On the other hand, the reaction of step (c) can be carried out bytreating the compound of Formula VIII with a dehydrogenating agent.Among the preferred dehydrogenating agents are included aluminumtert.-butylate or a benzoquinone substituted by halogen and/or cyano.Among the preferred dehydrogenating agents for use in this invention isdichlorodicyanobenzoquinone. The conditions which are commonly employedin utilizing these dehydrogenating agents can be utilized carrying outthe reaction of step (c).

In a further preferred embodiment the diol obtained is oxidized withmanganese dioxide to the desired l-hydroxy- 4-oxo compound of Formula I.In the performance of this reaction step the diol is dissolved in aninert organic solvent, for example methylene chlorides, manganesedioxide is added and the mixture is shaken, preferably at roomtemperature. In a preferred embodiment the mixture is shaken for 24hours and then worked up in a conventional manner.

The compounds of Formulae V, VI, VII, and VIH above can be respectivelyconverted to the compound of Formulae IX, X, XI, and I-A, by either aWittig or Horner reaction. In the reactions of steps (d), (e), (f) and(g) the compounds of Formulae V, VI, VII and VIII are reacted with aWittig reactant of the formula wherein X" is as X above with theexception of etherified and esterified hydroxymethylene or formyl, and RR and R are aryl or di-lower alkylamino; and Y is chlorine bromine oriodine or with a Horner reactant of the formula R4 R 1 -CHzX' 3 arewherein X' is cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl and Rand R are aryl, aryloxy or lower alkoxy.

In case a compound of Formula IX, X, XI or IA is desired, wherein X' isan etherified or esterified hydroxymethylene or a formyl group, therespective compounds of Formula XXIII, XXIV, XXV or XX are prepared asdescribed hereinafter and the esterified hydroxymethylene compoundobtained may be hydrolized and, if necessary, etherified or oxidizedwith manganese dioxide to the formyl derivative in conventional manners.

The Wittig or Horner reactions of steps ((1), (e), (f) and (g) can becarried out by conventional means well known in the art. Generally,these reactions are carried out in the presence of an alkali metal basein an inert organic solvent. Any conventional alkali metal base can beutilized. The conventional alkali metal bases include the alkali metalhydrides such as sodium hydride, potassium hydride; alkali metal loweralkoxides such as, sodium methoxide, sodium ethoxide, etc.; and thealkali metal amide bases such as, sodamide, potassium amide, sodiummethylamide, potassium methylamide, as well as other alkali metal loweralkyl amides. In carrying out either the Horner or Wittig reactions, anyconventional inert organic solvent can be utilized. Generally, solventssuch as benzene, toluene, tetrahydrofuran, dioxane, N,N-dimethylformamide are preferred. In carrying out either the Horner orWittig reactions, temperature and pressure are not critical and thesereactions can be carried out at room temperature and atmosphericpressure. If desired higher or lower temperatures can be utilized.

The conversion of compounds of the Formula IX to compounds of theFormula X, via reaction step (h) is carried out in the same manner asdescribed in connection with step (a). The conversion of compounds ofthe Formula X to compounds of the Formula XI via reaction step (i) iscarried out in the same manner as described in connection with step (b).The conversion of compounds of the Formula XI to compounds of theFormula I-A via reaction step (j), is carried out in the same manner asdescribed in connection with step (c).

When X in the compound of the Formula I-A is an etherifiedhydroxymethylene group, this group can be saponified to thecorresponding alcohol by conventional saponifying techniques such as bytreatment with a base. Among the preferred bases for carrying out thissaponification are included alkali metal lower alkoxides such as sodiummethoxide.

When X in the compound of Formula I-A is an ether ified hydroymethylenegroup, this group can be converted to the corresponding alcohol byconventional means such as by treating the ether with a concentratedaqueous hydrohalic acid such as hydrogen bromide or hydrogen iodide.This reaction is generally carried out by heating.

When X in the compound of Formula I-A is a lower alkoxycarbonyl,phenoxycarbonyl, or substituted phenoxycarbonyl, this ester can, ifdesired, be converted into amide (which may be lower alkyl substituted).This conversion can be carried out, for example, by treating the esterwith an appropriate dialkylamine lithium compound. The dialkylaminelithium compound needed for this reaction can expediently be prepared bydissolving a dialkylamine (e.g., diethylamine) in diethyl ether andmixing the resulting solution in the cold (preferably at -10 C. to 20C.) with a solution of butyl lithium in hexane or tetrahydrofuran andsubsequently allowing this mixture to react. The dialkylamine lithiumobtained is advantageously reacted with the ester at room temperature.

When X, in the compound of Formula I-A above is lower alkoxy carbonyl,phenoxycarbonyl, or surstituted phenoxycarbonyl, these esters can beconverted to the corresponding acid by saponification in the mannermentioned hereinbefore. The resulting acids can be converted into acidchlorides by conventional means such as by treatment with thionylchloride, preferably in the presence of pyridine. The acid halide can betransformed into an ester by reaction with a lower alkanoyl, phenol or asubstituted phenol. On theother hand, the acid halide can be transformedinto an acid amide by reaction with ammonia, a mono-substituted amine, adi-substituted amine or a cyclic amine such as imidazole, utilizingconventional procedures well known in the art.

In accordance with a preferred embodiment of this invention, anintermediate of the formula wherein R is as above, via a Wittig reactionwith a compound of the formula (XXII) wherein Y is chlorine, bromine oriodine to produce a compound of the formula (XXIV) wherein R is asabove, by treatment with an organic peroxide in the manner described inconnection with step (a). The compound of Formula XXIV is converted to acompound having the formula:

wherein R is as above, by treatment with selenium dioxide in the mannerdescribed in connection with step (b).

The compound of Formula XXV is converted to the compound of Formula XXby treatment with an oxidizing agent such as manganese dioxide or any ofthe other oxidizing agents as described in connection with step (c).

The following examples are illustrative of the invention and are not tobe construed as limited thereof. In the examples, all temperatures arein degrees centigrade. The term concentrated sulfuric acid as utilizedin the examples designates an aqueous solution containing 96% by weightof sulfuric acid. The petroleum ether utilized in these examples had aboiling point of -105 C. The term dilute sulfuric acid as utilized inthe examples is an aqueous solution containing 12% by weight of sulfuricacid.

(XXV) EXAMPLE 1 1.5 g. of4-(1,2-epoxy-2,6,6-trimethyl-cyclohex-3-en-lyl)-but-3-en-2-one(designated in the following by 5,6- epoxy-3,4-dehydro-B-ionone) aretreated with 25 ml. of abs. tetrahydrofuran and, after the addition of 3g. of pulverized selenium dioxide, shaken with nitrogen gassing for 12hours. The reaction mixture is thereupon diluted with 100 ml. of diethylether and then filtered. The filtrate is successively washed with 0.5 Naqueous sodium hydroxide and water, dried over sodium sulphate andevaporated under reduced pressure to produce 4-(1,4-dihydroxy 2,6,6trimethylcyclohex-2-en-1-yl)-but-3-en-2- one as a yellow oil.

EXAMPLE 2 The yellow oil4-(1,4-dihydroxy-Z,6,6-trimethyl-cyclohex-2-en-l-yl)-but-3-en-2-one istaken up in 50 ml. of acetone and subsequently treated at 0 C. with 1.13ml. of a chromic acid solution [26.72 g. of chromium trioxide, 23 ml. ofcone. sulphuric acid, water to 100 ml.]. After 5 minutes, the reactionmixture is poured onto ice and extracted with diethyl ether. The etherextract is successively washed with a saturated aqueous sodiumbicarbonate solution and with water, dried over sodium sulphate andevaporated under reduced pressure. The residual oily yellow-colored4-(1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-2-en-1-yl)-but-3-en-2-one ispurified by adsorption on the l00-fold amount of Kieselgel [elutingagent: hexane/ acetic acid ethyl ester 1:2]. After recrystallizationfrom benzene/hexane, the compound melts at 112 C.

9 EXAMPLE 3 19 g. of 4-(2,6,6-trimethyl-cyclohex-1,3-dien-1-yl)-but-3-en-2-one [3,4-dehydro- 8-ionone] are dissolved in 300 ml. of methylenechloride and, with stirring at 3 to 5 C., treated little by little with23.5 g. of m-chloroperbenzoic acid. The reaction mixture is furtherstirred at C. for 2 hours, then poured into a mixture of 300 ml. oficewater and 46 ml. of 3 N aqueous sodium hydroxide. The methylenechloride layer is separated olf and washed neutral with water. Theaqueous phase is exhaustively extracted with diethyl ether. The etherextract obtained, together with the methylene chloride phase, is driedover sodium sulphate and evaporated under reduced pressure. The residuallight-yellow colored oily 5,6-epoxy-3,4-dehydro-fi-ionone is purified byadsorption on the 50-fold amount of Kieselgel [granule size 0.2-0.5mm.]. [Eluting agent: hexane/ acetic acid ethyl ester 7:2 parts byvolume] EXAMPLE 4 3.2 g. of3-methyl-5-(1,2-epoxy-2,6,6-trimethyl-cyclohex-3-en-1-yl)-penta-2-cis/trans, 4-trans-dien-l-oic acid ethyl ester areintroduced into 50 ml. of tetrahydrofuran and, after the addition of 6.4g. of selenium dioxide, shaken at room temperature for 48 hours. Thereaction mixture is thereupon diluted with 150 ml. of diethyl ether andfiltered clear. The ethereal solution is washed three times with cold0.5 N aqueous sodium hydroxide and subsequently three times with water,dried over sodium sulphate and evaporated under reduced pressure. Thereresulted3-methyl-5-(1,4-dihydroxy-2,6,6-trimethyl-cyclohex-2-en-l-yl)-penta-2-cis/trans,4-trans-dien-1-oic acid ethyl ester as a yellow oil.

EXAMPLE 5 3.4 g. of 3-methyl-5-(1,4-dihydroxy-2,6,6-trimethylcyclohex 2en-l-yl) -penta-2-cis/ trans, 4-trans-dien-l-oic acid ethyl ester aredissolved in 100 ml. of acetone and treated at 0 C. with 4.33 ml. of achromic acid solution [26.72 g. of chromium trioxide, 23 ml. of cone.sulphuric acid, water to 100 ml.]. After 5 minutes, the reaction mixtureis poured onto ice and extracted with diethyl ether. The ether phase iswashed with saturated aqueous sodium bicarbonate solution then withwater, dried over sodium sulphate and evaporated under reduced pressure.The residual dark-yellow oily 3-methyl-5-(1-hydroxy-2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl)-penta 2 cis/ trans,4-trans-dien-1-oic acid ethyl ester can subsequently be saponified asfollows without further purification.

EXAMPLE =6 After the addition of a solution of g. of potassium hydroxidein 70 m1. of methanol and 30 ml. of water, 2.9 g. of3-methyl-5-(1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-Z-en-1yl)-penta-2-cis/trans,4-trans-dien-1-oic acid ethyl ester are stirred at room temperature for24 hours. The reaction mixture is subsequently concentrated underreduced pressure. The concentrate is taken up in Water and extractedwith diethyl ether. The aqueous phase is slightly acidified with dilutesulphuric acid and again extracted with diethyl ether. The last-obtainedether extract is Washed three times with water, decolorized with the aidof active charcoal, dried over sodium sulphate and treated withhigh-boiling petroleum ether up to incipient crystallization. The3-methyl-5-(1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-2-en-l-yl)-penta-2-cis-4-trans-dien-l-oicacid which precipitates melts at l85186 C.

EXAMPLE 7 3.85 g. of sodium hydride [50% by weight suspension in mineraloil] are overlaid with 150 ml. of abs. dioxan and treated dropwise at 10C. with 31 g. of di(2-chlorophenyl)-ethoxy-carbonyl-methyl-phosphineoxide. The mixture is stirred at room temperature for 30 minutes, thenagain cooled to 10 C. and treated dropwise with a solution of g. of5,6-epoxy-3,4-dehydro- 8-ionone [manufactured according to Example 3] in20 ml. of dioxan. The reaction mixture is stirred at room temperaturefor 12 hours, and after decomposition of the excess sodium hydride bycautious addition of ethanol, poured into an ice/sodium chloride mixtureand exhaustively extracted with diethyl ether. The ether extract iswashed with water, dried over sodium sulphate and evaporated underreduced pressure. The residual yellow, oily 3-methyl-5-(1,2-epoxy-2,6,6-trimethyl-cyclohex-3-en-1-yl)-penta- Z-cis/trans,4-trans-dien-1-oic acid ethyl ester is purified by adsorption on the-fold amount of Kieselgel [eluting agent: hexane/acetic acid ethyl ester7:1 parts by volume], B.P. about 165 C./0.05 mm. Hg.

EXAMPLE 8 6 g. of 3-methyl-5-(l,2-epoxy-2,6,G-trimethyl-cyclohex-3-en-1-yl)-penta-2-cis, 4-trans-dien-1-oic acid methyl ester aredissolved in ml. of dioxan and, after the addition of 5 g. of pulverizedselenium dioxide, stirred at room temperature for 50 hours. The reactionsolution is filtered clear. The filtrate is diluted with 250 m1. ofhexane and, after the addition of 6.2 g. of mercury (II) chloride,intensively stirred in ml. of water for 5 hours. The mixture issubsequently filtered. The filtrate is diluted with diethyl ether,washed neutral with water, dried over sodium sulphate and evaporatedunder reduced pressure. The residual isomer mixture consisted of3-methyl-5-(1,4- cisdihydroxy-2,6,6-trimethyl-cyclohex-2-en-l-yl)-penta- 2-cis,4-trans-dien-1-oic acid methyl ester and S-methyl-5-(1,4-trans-dihydroxy 2,6,6 trimethyl-cyclohex-2-en-1- yl)-penta-2-cis,4-trans-dien-l-oic acid methyl ester.

EXAMPLE 9 6.3 g. of the isomer mixture of 3-methyl-5-(l,4-cis/trans-dihydroxy-2,6,fi-trimethyl-cyclohex-Z-en-1-y1) -p enta- Z-cis,4-transdien-l-oic acid methyl ester are dissolved in 150 ml. of acetoneand treated at 0 C. with 8.45 ml. of a chromic acid solution [26.72 g.of chromium trioxide, 23 ml. of cone. sulphuric acid, Water to 100 ml.].After 10 minutes, the reaction mixture is poured onto ice and extractedwith diethyl ether. The ether extract is washed with a saturated aqueoussodium bicarbonate solution and with water, dried over sodium sulphateand evaporated. The residual yellow oily 3-methyl-5-(1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-2-en-l-yl) penta-Z-cis, 4-trans-dien-l-oic acid methyl ester is purified by adsorption on the40-fold amount of Kieselgel [eluting agent: hexane/acetic acid ethylester 1:1 parts by volume]. After recrystallization from high-boilingpetroleum ether with the addition of a little diethyl ether, the estermelts at 96 C.

EXAMPLE 10 After the addition of a solution of 6 g. of potassiumhydroxide in 45 ml. of methanol and 15 ml. of water, 1.8 g. of3-methyl-5-(1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-2-en-1-yl)-penta-2-cis,4-trans-dien-1oic acid methyl ester are stirred at room temperature for12 hours. The reaction mixture is thereupon diluted with water. Theaqueous phase is exhaustively extracted with diethyl ether. The waterphase is slightly acidified with dilute aqueous sulphuric acid andextracted with diethyl ether. The last obtained ether extract is washedthree times with water, dried over sodium sulphate and evaporated underreduced pressure. The residual 3-methyl-5-(1-hydroxy-2,6,6-trimethyl 4oxo-cyclohex-Z-en-l-yl)-penta-2-cis, 4-transdien-l-oic acid melts at187188 C. after recrystallization from hexane/diethyl ether.

EXAMPLE ll 6 g. of 3-methyl-5-(2,6,6-trimethyl-cyclohexa-1,3-dien-1-yl)-penta-2-cis, 4-trans-dien-1-oic acid methyl ester [prepared fromdi(2-chlorophenyl) methoxycarbonylmethyl-phosphine oxide and5,6-epoxy-3,4-dehydro-B- ionine as described in Example 9] are dissolvedin 60 ml. of methylene chloride and treated dropwise at 0 C.

1 1 with a solution of 5.3 g. of m-chloro-perbenzoic acid in 60 ml. ofmethylene chloride. The reaction mixture is further stirred at C. for 90minutes, then poured into a mixture of ice and ml. of 3 N aqueous sodiumhydroxide. The methylene chloride layer is separated off, washed withwater, dried over sodium sulphate and evaporated under reduced pressure.The residual yellow, oily 3- methyl-5-(1,2-epoxy 2,6,6trimethyl-cyclohex-3-en-1- yl)-penta-2-cis, 4-trans-1-oic acid methylester can be purified by adsorption on the 40-fold amount of Kieselgel[eluting agent: hexane/ acetic acid ethyl ester 9:1].

EXAMPLE 12 29g. of 3-methyl-5-(2,6,6-trimethyl-cyclohexa-1,3-dienl-yl)-penta-2,4-diene-1-al wasdissolved in 50 m1. of methylene chloride and at 0 2.3 g. ofm-chloroperbenzoic acid were added. The temperature rose to 8". Thereaction mixture was allowed to stand at 0 for 1 hour and then pouredonto ice and 5 ml. of 3 N aqueous sodium hydroxide. After extractionwith ether, the organic phase was washed with water, dried andevaporated to dryness. The crude product was chromatographed on 40-foldamount of aluminium oxide (neutral, activity grade III (Woelm) withhexane/acetic acid ethyl ester -(6: 1)

The crude, light yellow oil was used directly for the next step asdescribed in Examples 1, 4 and 14.

EXAMPLE 13 By the procedure of Examples 1, 2 and 3:

3-methyl 5 (2,6,6-trimethyl-cyclohexa-1,3-dien-1-yl)-penta-2,4-dien-1-oic acid n-pentyl ester is converted to3-methyl-5-(l,2-epoxy 2,6,6 trimethyl-cyclohex-3-en-1-yl)-penta-2,4-dien-l-oic acid n-pentyl ester, which then isconverted to 3-mcthyl-5-(1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex 2en-l-yl)-penta-2,4-dien-l-oic acid n-pentyl ester [oil];3-methyl-5-(2,6,6-trimethylcyclohexa-1,3-dien-l-yl)-penta-2,4-dien-1-oicacid phenyl ester [M.P. 161- 166 0.];3-methyl-5(2,6,6-trimethylmethyl-cyclohex-B-en-l-yl)-penta 2,4dien-l-oic acid phenyl ester which then is converted to 3-methyl-5-(1-hydroxy-2,6,6-trimethyl 4 oxo-cyclohex-2-en-1-yl)- penta-2,4-dien-1-oicacid phenyl ester [M.P. l46147 C.] 3-methyl-5-(2,6,6-trimethyl-cyclohexa-1,3-dien-1-yl)- penta-2,4-dien-1-oic acidp-nitrophenyl ester is converted to3-methyl-5-(1,2-epoxy-2,6,6-trirnethyl-cyclohex-3-en-1-yl)-penta-2,4-dien-l-oicacid p-nitrophenyl ester which then is converted to3-methyl-5-(1-hydroxy- (2,6,6-trimethyl-cyclohexa-1,3-dien 1yl)-penta-ZA- dien-l-oic acid p-nitrophenyl ester [M.P. 158-163 C.];3-methyl 5 (2,6,6-trimethyl-cyclohexa-1,3-dien-l-y1)-penta-2,4-dien-1-oic acid p-methyl sulfonyl-phenyl ester is converted to3-methyl5-(1,2-epoxy-2,6,6-trimethy1-cyclohex-3-en-1-yl)-penta-2,4-dien-1-oic acid p-methylsulfonyl-phenylester which then is converted to 3-methyl-5-(1-hydroxy-2,-6,6-trimethyl-4-oxo-cyclohex 2en-lyl)-penta-2,-4-dien-1-oic acid p-methyl sulfonyl-phenylester [M.P.161-166 C.];3-methyl-5-(2,6,6-trimethylcyclohexa-1,3-dien-l-yl)-penta-2,4dien-1-oicacid-nitrile is converted to3-methyl-5-(1,2-epoxy-2,6,6-trimethylcyclohex-3-en-l-yl)-penta-2,4-dien-l-oicacid-nitrile which then is converted to3-methyl-5-(1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex 2en-l-yl)-penta-2,4-dien-1-oic acid-nitrile [M.P. 172-173 C.];1-benzoyl-3-methyl-5- (2,6,6-trimethyl-cyclohexa-1,3-dien 1yl)-penta-2,4- dien is converted to l-benzoyl 3-methyl-5-(l,2-epoxy-2,6,6trimethyl-cyclohex-3en-l-yl)penta-2,4-diene which then is convertedto 1-benzoyl-3-methyl-5-(l-hydroxy- 2,6,6-trimethyl-4oxo-cyclohex 2en-1-yl)-penta-2,4- dien [oil];3-methyl-5-(2,6,6-trimethyl-cyclohexa-1,3-dienl-yl)-penta-2,4-dien-1-oic acid-imidazolide is converted to3-methyl-5-(1,2-epoxy-2,6,6-trimethyl-cyclohex-3-en-1-y1)-penta-2,4-dien-1-oic acid-imidazolide which then is convertedto 3-methyl-5-(1-hydroxy-2,6,6-tri- 12methyl-4-oxo-cyclohex-Z-en-l-yl)-penta 2,4 dien-l-oic acid-imidazolide[M.P. 165-175 C.]; and 3-methyl-5- (2,6,6-trimethyl-cyclohexa-1,3-dien 1yl)-penta-2,4- dien-l-al is converted to3-methyl-5-(l,2-epoxy-2,6,6-trimethyl-cyclohex-3-en-l-yl)-penta-2,4-dien-l-alwhich then is converted to 3-methyl-5-(l-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-Z-en-l-yl)-penta-2,4dien-l-a1 [M.P. 113- 115 0.].

EXAMPLE 14 In 60 ml. of tetrahydrofuran, there was dissolved 2.8 g. of3-methy1 5 (1,2-epoxy 2,6,6 trimethyl-cyclohex-3-en-1-yl)penta 2,4dienyl acetate. After the addition of 6.5 g. of selenium dioxide, themixture was allowed to stand for 45 hours at room temperature. Afterthis period, the reaction mixture 'was diluted with ml. of diethyl etherand filtered. The ether solution was washed 3 times with 0.5 N aqueoussodium hydroxide and then 3 times with Water. The reaction mixture wasthen dried over sodium sulfate and then evaporated under vacuum. Afterevaporation, there resulted 3-methy1-5- (1,4-dihydroxy 2,6,6trimethyl-cyclohex 2 en-1-yl)- penta-2,4-dienyl acetate as a crude oil.

EXAMPLE 15 In 100 ml. of methylene chloride there was dissolved 3 g. of3 methyl 5 (1,4 dihydroxy 2,6,6 trimethylcyclohex 2 en 1 yl) penta 2,4dienyl acetate and 30 :g. of manganese dioxide. The resulting reactionmixture was shaken for 24 hours at room temperature. After this period,the reaction mixture was filtered and then evaporated to dryness undervacuum. From the resulting oily product, B-methyl 5 (l-hydroxy-2,6,6-trimethyl 4 oxo-cyclohex-Z-en-l-yl)-penta 2 cis-4- trans-dienyl acetatewas obtained. This product was ob tained in crystalline form byfractional crystallization from a mixture of hexane and diethyl ether.The resulting product had a melting point of 100 101 C.

EXAMPLE 16 In 20 ml. of methanol, there was dissolved 2 g. of 3- methyl5 -(1 hydroxy 2,6,6 trimethyl-4-oxo-cyclohex-2-en-1-yl)-penta 2 cis 4transdienyl acetate. After the addition of 15 g. of sodium hydroxide in5 ml. of water to the solution, the reaction mixture was allowed tostand for one hour at room temperature under constant stirring. Afterthis, 100 ml. of Water were added to the solution and the solution wasextracted with diethyl ether. The resulting ether solution was washedneutral with water and then dried by evaporation under vacuum. From theresidue, the product '3-methyl 5 (1- hydroxy 2,6,6 trimethyl 4oxo-cyclohex-2-en-1-yl)- penta 2 cis 4 trans-dien-l-ol was crystallizedutilizing a mixture of hexane and acetic acid ethyl ester. The producthad a melting point of 126128 C.

EXAMPLE 17 50 g. of 3,4 dehydro cyclogeranyl-triphenyl phosphoniumbromide, which was obtained by reacting equimolar amounts of 3,4dehydro-cyclogeranyl bromide (1- bromomethyl 2,6,6 trimethyl-cyclohexa1,3 diene) with triphenyl phosphine, was dissolved in 250 ml. ofdimethyl formamide. To the resulting solution there was added a solutioncontaining 2.3 g. of sodium in 75 ml. of absolute alcohol. After thesodium ethoxide solution 'was added, 14 g. of 3-formyl-2-butenyl acetatein 20 ml. of dimethyl formamide was added to the reaction mixture. Theresulting reaction mixture was stirred for 5 hours at 0 C. and thenacidified with a dilute sulfuric acid solution. There resulted a lightyellow oily suspension which was extracted with hexane. The hexaneextract was washed neutral with water and then dried over sodiumsulfate. The solvent was removed from the reaction medium by evaporationutilizing vacuum. After evaporation, a light oil resulted. This oil waspurified by adsorp- 13 tion on Kieselgel and eluting with benzene. Theresulting product was 3-methyl -5 (2,6,6-trimethyl-cyclohexa1,3-diene-l-yl) -penta-2,4-dienyl acetate.

EXAMPLE 1 8 In 200 ml. of methylene chloride there was dissolved 12 g.of 3-methyl 5 (2,6,6 trimethyl-cyclohexa-1,3-dien- 1-yl)penta 2,4 dienylacetate. The resulting solution was cooled to C. At this temperature 5.6g. of mchloroperbenzoic acid was added protionwise. The reaction mixturewas allowed to stand for 60 minutes at 0 C. under constant stirring andpoured on a mixture of ice and 20 m1. of 3 N aqueous sodium hydroxide.After this period, the methylene chloride phase was separated and washedwith water. After washing, this phase was dried over sodium sulfate andevaporated under reduced pressure. After evaporation there resulted3-methyl-5- (1,2 epoxy 2,6,6 trimethylcyclohex 3 en-1-yl)-penta-2,4-dienyl acetate as a yellow oil. This yellow oil was purifiedby adsorption on a 50 fold amount of Kieselgel (elution agent:hexane/acetic acid ethyl ester 10:1 parts by volume).

EXAMPLE 19 In the manner of Examples 18, 14 and 15 3-methyl(2,6,6-trimethyl-cyclohexa-1,3-dien-1-yl)- penta-2,4-dienyl benzoate wasconverted to 3-methyl-5- (l,2-epoxy-2,6,6-trimethyl-cyclohex 3 en1-yl)-penta- 2,4-dienyl benzoate which then was converted to3-methyl-5-(1-hydroxy-2,6,6-trimethyl 4 oxo-cyclohex-2-en-1-yl)-penta-2,4-dienyl benzoate (M.P. 105); 3-methyl-5- (2,6,6trimethyl-cyclohexa 1,3 dien-1-yl)-penta-2,4- dienyl-2,4'-dinitrobenzoate was converted to 3-methyl-5-(1,2-epoxy-2,6,6-trimethyl-cyclohex 3 en 1 yl)-penta-2,4-dienyl-2,4'-dinitro benzoate which then was converted to3-methyl-5-(1-hydroxy 2,6,6 trimethyl-4-oxo-cyclohex-Z-en-l-yl)-penta-2,4-dienyl 2',4' dinitro benzoate (M.P.130-131"); 3-methyl-5-(2,6,6-trimethylcyclohexa-1,3-dien-1-yl)-penta 2,4dienyl naphthoate was converted to3-methyl-5-(1,2-epoxy-2,6,6-trimethylcyclohex-3-en-1-yl)-penta-2,4-dienylnaphthoate which then was converted to3-methyl-5-(1-hydroxy-2,6,6-trimethyl 4 oxo-cyclohex-Z-en-l-yl)-penta2,4 dienyl naphthoate (M.P. 126-127")3-methyl-5-(2,6,6-1Iimethylcyclohexa-1,3-dien-1-yl)-penta 2,4 dienyl4-methyl benzoate was converted to 3-methyl-5-(1,2-epoxy-2,6,6-trimethyl-cyclohex-3-en-l-yl) -penta 2,4-dienyl-4'-methyl benzoate whichthen was converted to 3-methyl-5-(1-hydroxy-2,6,6-trimethyl 4oxo-cyclohex-Z-en-l-yl)-penta- 2,4-dienyl-4'-methyl benzoate (M.P. 119);3-methyl-5- (2,6,6 trimethyl-cyclohexa 1,3 dien-1-yl)-penta-2,4-dienyl-4-chloro benzoate was converted to 3-methyl-5- (1,2-epoxy 2,6,6trimethy1-cyclohex-3-en-1-y1)-penta- 2,4-dienyl-4'-chloro benzoate whichthen was converted to 3-methyl-5-(1-hydroxy-2,6,6-trimethyl 4oxo-cyclohex-2-en-1-yl)-penta-2,4dienyl-4-chloro benzoate (M.P. 1233-methyl-5-(2,6,6-trimethyl-cyclohexa-1,3-dien-1-yl)-penta-2,4-dienyl-4'-nitro benzoate was converted to3-methyl-5-(1,2-epoxy 2,6,6trimethyl-cyclohex-3-enl-yl)-penta-2,4-dienyl-4'-nitro benzoate whichthen was converted to 3-methyl-5-(1-hydroxy 2,6,6 trimethyl-4-oxo-cyclohex-Z-en-1-y1)-penta-2,4-dienyl 4-nitro benzoate (M.P.135-136);3-methyl-5-(2,6,6-trimethy1-cyclohexa-1,3-dien-1-yl)-penta-2,4-dienyl-chloroacetate was converted to3-methyl-5-(1,2-epoxy-2,6,6-trimethyl-cyclohex-3-en-l-yl)-penta-2,4-dienyl-chloroacetate which then was converted to3-methy1-5-(l-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-2-en-1-yl)-penta-2,4-dienyl-chloro acetate EXAMPLE 20 Allof the products in Example 19 were utilized by the procedure of Example16 to produce 3-methyl-5-(1-hy- 14 droxy-2,6,6-trimethyl 4oxo-cyclohex-Z-en- 1-y1)-penta- 2,4-dien-l-ol.

What is claimed is: 1. A process for producing a compound of theformula:

Xis

R: R and R are individually hydrogen, lower alkyl, or phenyl or takentogether with their attached nitrogen atom form an imidazole ring; R islower alkyl or phenyl; and R is lower alkyl, halo-lower alkyl, phenyl orphenyl substituted with alkyl, halogen or nitro;

comprising reacting a compound of the formula:

wherein R is as above; with selenium dioxide in an inert solvent.

2. The process of claim 1 wherein said reaction is carried out underanhydrous conditions.

3. The process of claim 2 wherein the reaction is carried out intetrahydrofuran.

4. The compound4-(1,4-dihydroxy-2,6,6-trimethyl-cyclohex-Z-eu-l-yl)-but-3-en-2-one.

References Cited UNITED STATES PATENTS 3,400,158 9/1968 Roberts 2605873,607,942 9/1971 Rowland 260-587 3,410,908 11/ 1968 Rowland et al 260587FOREIGN PATENTS 708,294 5/ 1954 Great Britain 260-687 403,838 3/ 1933Great Britain 260-587 731,669 4/1966 Canada 260587 BERNARD HELFIN,Primary Examiner N. MORGENSTERN, Assistant Examiner US. Cl. X.R.

2-60240 J, 309.6, 348 A, 348 C, 456 R, 464, 468 A, 469,

471 R, 484R, 487, 488 R, 514R, 557 R, 559R, 598,

